The proposed renewal application, entitled MRI, Cognitive, Genetic and Biomarker Precursors of AD & Dementia in Young Adults seeks to extend the study of preclinical dementia to a community-based sample of younger aged adults decades before possible onset of clinical symptoms. In the previous grant cycle, the Framingham Heart Study Generation 3 and its smaller multi-ethnic Omni Generation 2 cohorts were administered a neuropsychological test battery (NP; n=2498) and a brain MRI scan (n=2279). These cohorts had been previously characterized in detail through their participation in two health examinations, administered between 2002-2009, in which numerous lifestyle, genetic and circulating biomarkers have been measured. By proposing a repeat administration of the NP and MRI protocols we will establish the first population cohort able to estimate the heterogeneity of change in detectable differences in cognitive performance and brain structure. To meet this primary aim of earlier detection, we have incorporated novel cognitive indices that include error responses and latency metrics acquired through participant use of a digital pen and predict that for persons in whom change is evident, we will observe at least three distinct cognitive phenotypes - amnestic, executive function, and mixed, based on traditional and novel neuropsychological test performance measures. For detecting MRI changes, we will not only evaluate longitudinal measures but also construct a measure of brain structural health based on combined measures of white matter hyperintensities, gray matter regional volumes, cortical thickness and fractional anisotropy measures in specified regions. Another central aim of this proposal is to determine whether early vascular risk and other health measures, genetic factors and newer biomarkers are predictive of incident decline in cognition and brain morphology previously linked to increased risk of AD. Finally, we will test novel computational analytic methods to construct multi-marker preclinical risk scores predictive of cognitive and neuroimaging changes. Dementia is not an inevitable consequence of brain aging and determining the earliest age in which brain aging is detectable and the risk factors related to these early signs of change may lead to new pathways for intervention and prevention.